The present invention relates to imidazolidine derivatives which are useful as medicaments, more particularly as phosphatidylinositol-3-kinase (PI3K) inhibitors and antitumor agents.
Phosphatidylinositol (hereinafter abbreviated as xe2x80x9cPIxe2x80x9d) is one of a number of phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. It is well recognized in the art that especially PI (4,5) bisphosphate (PI(4,5)P2) is degraded into diacylglycerol and inositol (1,4,5) triphosphate by phospholipase C to induce activation of protein kinase C and intracellular calcium mobilization, respectively [M. J. Berridge et al., Nature, 312, 315 (1984); Y Nishizuka, Science, 225, 1365 (1984)].
Turning back to the late 1980s, a PI3 kinase (PI3K) was found to be an enzyme to phosphorylate the 3-position of the inositol ring of phosphatidylinositol [D. Whitrnan et al., Nature, 332, 664 (1988)].
PI3K was originally considered to be a single enzyme at the time when PI3K was discovered. Recently it was clarified that a plurality of subtypes are present in the PI3K. Three major classes of PI3Ks have now been identified on the basis of their in vitro substrate specificity [B. Vanhaesebroeck, Trend in Biol. Sci., 22, 267(1997)].
Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2. In these substrates, PI(4,5)P2 is the most advantageous substrate in cells. Class I PI3Ks are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PI3Ks, which include PI3K p110xcex1, p110xcex2 and p110xcex4 subtypes, are activated in the tyrosine kinase system. Class Ib PI3K includes a p110xcex3 subtype activated by a G protein-coupled receptor.
PI and PI(4)P are known as substrates for class II PI3Ks but PI(4,5)P2 is not a substrate for the enzymes of this class. Class II PI3Ks include PI3K C2xcex1, C2xcex2 and C2xcex3 subtypes, which are characterized by containing C2 domains at the C terminus, implying that their activity will be regulated by calcium ions. The substrate for class III PI3Ks is PI only. A mechanism for activation of the class III PI3Ks is not clarified yet. Since each subtype has its own mechanism for regulating activity, it is considered that the respective subtypes will be activated depending on their respective stimuli specific to each of them.
In the PI3K subtypes, the class la subtype has been most extensively investigated to date. The three subtypes of class la are hetero dimers of a catalytic 110 kDa subunit and regulatory subunits of 85 kDa and 55 kDa. The regulatory subunits contain SH2 domains and bind to tyrosine residues phosphorylated by growth factor receptors with a tyrosine kinase activity or oncogene products thereby inducing the PI3K activity of the p110 catalytic subunit. Thus, the class Ia subtypes are considered to be associated with cell proliferation and carcinogenesis. Furthermore, the class Ia PI3K subtypes bind to activated ras oncogene to express their enzyme activity. It has been confirmed that the activated ras oncogene is found to be present in many cancers, suggesting a role of class Ia PI3Ks in carcinogenesis.
As explained above, the PI3K inhibitors are expected to be a new type of medicaments useful for cell proliferation disorders, in particular antitumor agents. As the PI3K inhibitor, wortnannin[H. Yano et al., J. Biol. Chem., 263, 16178 (1993)] and Y294002 [J. Vlahos et al., J. Biol. Chem., 269, 5241(1994)] which is represented by the formula below are known. However, creation of PI3K inhibitors are sincerely desired having a more potent and excellent cancer cell growth inhibiting activity. 
Japanese patent KOKAI (Laid-Open) No. H09-176165 discloses imidazopyridine derivatives having an ACAT inhibitory activity. WO93/25553 discloses imidazopyridine derivatives having an activity to treat atherosclerosis or hypercholesterolemia. U.S. Pat. No. 4,713,381 discloses imidazopyridine derivatives as reaction intermediates. However, all of these have a different structure from those of the compounds of the present invention. Further, these references do not disclose or imply a PI3K inhibiting and antitumor activity.
Hungarian patent publication No. HU 43066A2 and Eur. J. Med. Chem. (1989), 24(1), 97-9 discloses imidazopyridine derivatives substituted by a substitited-amino-substituted-1,3,5-triazinyl group having a cardiotonic activity. Arch. Pharm. (Weinheim, Ger.) (1992), 325(9), 623-4 discloses imidazopyridine derivatives substituted by a substitited-amino-substituted-1,3,4-oxadiazolyl which are useful as anticonvulsants. Moreover, the Maybridge catalogue (order No. SPB-04848) discloses imidazopyridine derivatives substituted by an alkylthio-substituted-pyrimidinyl group.
The present inventors have performed extensive investigations on compounds with a PI3K inhibiting activity. As a result, it has been discovered that novel imidazopyridine derivatives have an excellent PI3K inhibiting activity and cancer cell growth inhibiting activity. Based on the discovery, it has been found that the imidazopyridine derivatives could be excellent PI3K inhibitors and cancinostatic agents. The present invention has thus been achieved.
Therefore, the present invention relates to novel imidazopyridine derivatives or salts thereof which are useful as PI3K inhibitors and antitumor agents. The imidazopyridine derivatives are represented by the following general formula (I): 
wherein R1 represents xe2x80x94H, -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -a cycloalkenyl, -a halogen, xe2x80x94NO2, xe2x80x94CN, -a halogenated lower alkyl, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94SO2Ra, xe2x80x94SORa, xe2x80x94CO2Ra, xe2x80x94COxe2x80x94Ra, -an aryl, -a lower alkylene-an aryl, xe2x80x94O-a lower alkylene-an aryl, xe2x80x94CONRaRb, xe2x80x94CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94SO2NRaRb, xe2x80x94SO2-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94SO3H, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94NRaRb, xe2x80x94CONRa-a lower alkylene-ORb, xe2x80x94CONRa-a lower alkylene-NRbRc, xe2x80x94CONRa-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94O-a lower alkylene-ORa, xe2x80x94O-a lower alkylene-O-a lower alkylene-Oa, xe2x80x94O-a lower alkylene-NRaRb, xe2x80x94O-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94O-a lower alkylene-O-a lower alkylene-NRaRb, xe2x80x94O-a lower alkylene-O-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94O-a lower alkylene-NRc-a lower alkylene-NRaRb, xe2x80x94O-a lower alkylene-NRc-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94OCOxe2x80x94NRaRb, xe2x80x94OCO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94NRaxe2x80x94SO2Rb, xe2x80x94NRc-a lower alkylene-NRaRb, xe2x80x94NRc-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94N(a lower alkylene-NRaRb)2, xe2x80x94N(a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group))2, xe2x80x94CONRaxe2x80x94ORb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94NRaCOxe2x80x94NRbRc, xe2x80x94NRaxe2x80x94CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), or xe2x80x94OCORa;
Ra, Rb and Rc which may be the same or different, represent xe2x80x94H, -a lower alkyl or -an aryl;
T represents N or CR1a;
U represents N or CR3;
n represents an integer, 1, 2 or 3;
in Y . . . Y2 . . . Y3,
i) . . . represents a single bond on one side and a single or double bond on the other side, Y1 represents CR5 or CR5aR5b, Y2 represents N, NH, CR4a or CR4bR4c, and Y3 represents N R6, CR4d or CR4eR4f, whereas Y3 represents NR6 when Y2 represents CR4a or CR4bR4c, or, ii) Y1 and Y3 may be bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a B ring, wherein the B ring represents a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and O, a nitrogen-containing saturated heterocyclic ring or an aryl ring, whereas said B ring may be substituted by one to two R4s;
X represents S, SO or SO2, whereas X may also represent CO, NR7 or a methylene group when Y1 and Y3 are bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form the B ring;
xe2x80x9cAxe2x80x9d represents a linkage, a lower alkylene, a lower alkenylene or a lower alkenylene;
R2 represents -a lower alkyl which may have one or more subsituents, -a lower alkenyl which may have one or more subsituents, -a lower alkynyl which may have one or more subsituents, -a cycloalkyl which may have one or more subsituents, -a cycloalkenyl which may have one or more subsituents, xe2x80x94Nxe2x95x90O, -an aryl which may have one or more subsituents, or -a heteroaryl which may have one or more subsituents;
R1a, R3, R4a, R4c, R4d, R4e, R4f, R5a, and R5b, which may be the same or different, represent a group defined by R1, whereas R4b and R4c, R4e and R4f, or R5a and R5b may be combined with each other to form an oxo group (xe2x95x90O);
R4 represents a group defined by R1, or an oxo group (xe2x95x90O);
R5, R6, and R7, which may be the same or different, represent xe2x80x94H, -a lower alkyl which may have one or more subsituents, -a lower alkenyl which may have one or more subsituents, -a lower alkynyl which may have one or more subsituents, with proviso that when X is NR7 and R2 is an aryl having a substituent at the ortho-position, R7 may be combined with the substituent at the ortho-position to form a C2-3 lower alkylene chain, and with the aryl of R2 to form a 5- to 7-membered nitrogen-containing heterocyclic ring fused with a benzene ring(s) of the aryl group;
with the proviso that
(1) X represents a group other than NR7 when Y1 . . . Y2 . . . Y3 is bonded with X via N atom or Y1 and Y3 are bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a 1,3,5-triazine or 1,3,4-oxadiazole ring; and
(2) X represents SO, SO2, CO or a methylene group when Y1 and Y3 are bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a pyrimidine ring.
The present invention further relates to novel pharmaceutical compositions, particularly to PI3K inhibitors and antitumor agents, comprising an imidazopyridine derivative of formula (1) above or a salt thereof and a pharmaceutically acceptable carrier.
A further aspect of the present invention relates to treatment methods of disorders (especially cancers) influenced by PI3K, wherein an effective amount of a novel imidazopyridine derivative of formula (1) above or a salt thereof is administered to humans or animals.
The compounds of general formula (I) are described below in more detail.
The term xe2x80x9clowerxe2x80x9d throughout the specification is used to mean a straight or branched hydrocarbon chain having 1 to 10, preferably 1 to 6, and more preferably 1 to 3 carbon atoms.
Preferred examples of the xe2x80x9clower alkylxe2x80x9d are an alkyl having 1 to 6 carbon atoms, more preferably methyl and ethyl. Preferred examples of the xe2x80x9clower alkenylxe2x80x9d include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl. Preferred examples of the xe2x80x9clower alkynylxe2x80x9d include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl. Examples of the xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkenylxe2x80x9d are preferably a cycloalkyl and a cycloalkenyl, each having 3 to 8 carbon atoms, more preferably cyclopropyl, cyclopentyl, cyclohexyl and cyclopentenyl. Preferred examples of the xe2x80x9clower alkylenexe2x80x9d include methylene, ethylene, trimethylene and 2,2-dimethyltrimethylene. The xe2x80x9clower alkenylenexe2x80x9d is preferably vinylene. The xe2x80x9clower alkenylenexe2x80x9d is preferably ethynylene.
The term xe2x80x9carylxe2x80x9d is used throughout the specification to mean an aromatic cyclic hydrocarbon group. An aryl having 6 to 14 carbon atoms is preferable. It may be partially saturated. Preferred examples of such aryl are phenyl and naphthyl. When Y1 and Y3 are bonded via 2 or 3 atoms and combined with the adjacent Y2 to form a B ring, a preferred aryl ring of the B ring is a benzene and naphthalene ring.
The xe2x80x9cheteroarylxe2x80x9d throughout the specification includes a 5- or 6-membered monocyclic heteroaryl having 1 to 4 hetero atoms selected from the group consisting of N, S and O as well as a bicyclic heteroaryl in which such a monocyclic heteroaryl is fused to a benzene ring. The heteroaryl may be partially saturated. A 5- to 6-membered monocyclic heteroaryl having 1 to 4 hetero atoms selected from the group consisting of N, S, and O is preferably exemplified by groups of furyl, thienyl, pyrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl. Examples of the bicyclic heteroaryl are preferably benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl and benzodioxolyl. Specific examples of the partially saturated heteroaryl are 1,2,3,4-tetrahydroquinolyl, etc. Particularly preferred as a heteroaryl in R2 are thienyl, pyrazolyl, thiazolyl, isoxazolyl, pyridyl, benzothiadiazolyl and quinolyl.
A xe2x80x9c5- to 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and Oxe2x80x9d in a B ring formed by bonding Y1 with Y3 via 2 or 3 atoms and combining Y1 and Y3 with the adjacent Y2 is a heteroaryl ring forming the aforementioned xe2x80x9c5- to 6-membered monocyclic heteroaryl having 1 to 4 hetero atoms selected from the group consisting of N, S, and Oxe2x80x9d. Preferable examples are a furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, pyridazine and pyrazine ring. More preferable examples are a 5-membered monocyclic heteroaryl ring. Among them, more preferable examples are a pyrrole, imidazole, pyrazole, thiazole, oxazole and triazole ring, and particularly preferable examples are a pyrazole and thiazole ring.
Examples of the xe2x80x9chalogenxe2x80x9d are F, Cl, Br and I. Examples of the xe2x80x9chalogenated lower alkylxe2x80x9d are the aforementioned lower alkyl groups which are further substituted by one or more halogen atoms described above, preferably xe2x80x94CF3.
The xe2x80x9cnitrogen-containing saturated heterocyclic groupxe2x80x9d throughout the specification is a 5- to 7-membered heterocyclic group containing one or two nitrogen atoms on the ring, which may further contain one O or S atom and may form a bridge structure. Preferred examples of such heterocyclic group are 1-pyrrolidinyl, 1-piperazinyl, piperidino and morpholino. The xe2x80x9c5- to 7-membered nitrogen-containing heterocyclic ring fused with a benzene ring(s) of the aryl groupxe2x80x9d which is formed by combining R7 xe2x80x9cwith the substituent at the ortho-position to form a C2-3 lower alkylene chain, and with the aryl of R2xe2x80x9d xe2x80x9cwhen X is NR7 and R2 is an aryl having a substituent at the ortho-positionxe2x80x9d includes the above defined xe2x80x9cnitrogen-containing saturated heterocyclic groupxe2x80x9d fused with an aryl ring(s), preferably 1-pyrrolidinyl and piperidino fused with a benzene ring. The xe2x80x9cnitrogen-containing saturated heterocyclic groupxe2x80x9d in the B ring formed by bonding Y1 with Y3 via 2 or 3 atoms and combining Y1 and Y3 with the adjacent Y2 is preferably a pyrrolidine, imidazolidine or pyrazolidine ring and more preferably is a pyrrolidine ring.
The subsituents in the xe2x80x9clower alkyl which may have one or more subsituentsxe2x80x9d, xe2x80x9clower alkenyl which may have one or more subsituentsxe2x80x9d and xe2x80x9clower alkynyl which may have one or more subsituentsxe2x80x9d are 1xcx9c5 subsituents selected from Group D below.
Group D: -a halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94O-a lower alkyl, xe2x80x94O-a halogenated lower alkyl, xe2x80x94SH, xe2x80x94S-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94SO-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl, xe2x80x94CONH2, xe2x80x94NH2, xe2x80x94NH-a lower alkyl, xe2x80x94N(a lower alkyl)2, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), -an aryl, -a heteroaryl, -a cycloalkyl and -a cycloalkenyl. The same applies hereinafter.
The substituent(s) for xe2x80x9c-a cycloalkyl which may have one or more subsituentsxe2x80x9d, xe2x80x9c-a cycloalkenyl which may have one or more subsituentsxe2x80x9d, xe2x80x9c-an aryl which may have one or more subsituentsxe2x80x9d, and xe2x80x9c-a heteroaryl which may have one or more subsituentsxe2x80x9d shown by R2 are preferably -a lower alkyl which may have 1xcx9c5 substituents which are selected from Group D, -a lower alkenyl which may have 1xcx9c5 substituents which are selected from Group D, -a lower alkynyl which may have 1xcx9c5 substituents which are selected from Group D, -a cycloalkyl which may have 1xcx9c5 substituents which are selected from Group E, -a cycloalkenyl which may have 1xcx9c5 substituents which are selected from Group E, -a halogen, xe2x80x94NO2, xe2x80x94CN, -a halogenated lower alkyl, xe2x80x94O-a halogenated lower alkyl, xe2x80x94OH, xe2x80x94O-a lower alkyl, xe2x80x94SH, xe2x80x94S-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94SO-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CHO, xe2x80x94CO-a lower alkyl, xe2x80x94SO3H, xe2x80x94Ar1, xe2x80x94Oxe2x80x94Ar1, xe2x80x94Sxe2x80x94Ar1, xe2x80x94COxe2x80x94Ar1, xe2x80x94SO2xe2x80x94Ar1, xe2x80x94SOxe2x80x94Ar1, -a lower alkylene-Ar1, xe2x80x94O-a lower alkylene-Ar1, xe2x80x94CONH2, xe2x80x94CONH-a lower alkyl, xe2x80x94CON(a lower alkyl)2, xe2x80x94SO2NH2, xe2x80x94SO2NH-a lower alkyl, xe2x80x94SO2N(a lower alkyl)2, xe2x80x94CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94SO2-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94NH2, xe2x80x94NH-a lower alkyl, xe2x80x94N(a lower alkyl, xe2x80x94NHCO-a lower alkyl, xe2x80x94NHCOxe2x80x94Ar1, xe2x80x94NHSO2-a lower alkyl, xe2x80x94NHSO2xe2x80x94Ar1, -azido and xe2x80x94Nxe2x95x90Nxe2x80x94Ar1, wherein Group E consists of -a lower alkyl, -a lower alkenyl, -a lower alkynyl and the substituents in said Group D, and wherein Ar1 is an aryl or a heteroaryl which may have 1 to 5 substituents selected from Group E. The same applies hereinafter.
When xe2x80x9cnxe2x80x9d is 2 or 3, R1 groups may be the same or different. When two R4 groups exist, each R4 group may be the same or different from each other.
R3, R4a, R4b, R4c, R4d, R4c, and R4f are preferably xe2x80x94H, xe2x80x94OH, or a lower alkyl. Alternatively, R4b and R4c may be combined with each other to form an oxo group (xe2x95x90O). As for R4, -a lower alkyl, xe2x95x90O, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl or xe2x80x94SO3H is preferred. As for R5 and R7, xe2x80x94H or a lower alkyl is preferred. As for R6, xe2x80x94H, -a lower alkyl or alkenyl group is preferred, wherein the lower alkyl or alkenyl group may be substituted by a substituent(s) selected from xe2x80x94O-a lower alkyl, xe2x80x94S-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94SO-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl, xe2x80x94CONH2, xe2x80x94NH2, xe2x80x94NH-a lower alkyl, xe2x80x94N(a lower alkyl)2, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group) and -an aryl.
Preferred imidazopyridine derivatives of the present invention are compounds of formula (I) as below.
(1) Compounds in which R1 is xe2x80x94H, -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -a cycloalkenyl, -a halogen, xe2x80x94NO2, xe2x80x94CN, -a halogenated lower alkyl, xe2x80x94OH, xe2x80x94O-a lower alkyl, xe2x80x94O-an aryl, xe2x80x94SH, xe2x80x94S-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94SO-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl, -an aryl, xe2x80x94CO-an aryl, -a lower alkylene-an aryl, xe2x80x94O-a lower alkylene-an aryl, xe2x80x94CONH2, xe2x80x94SO2NH2, xe2x80x94SO3H, -a nitrogen-containing saturated heterocyclic group, xe2x80x94NH2, xe2x80x94NH-a lower alkyl or xe2x80x94N(a lower alkyl)2; T is CR1a; U is CR3; in Y1 Y2 Y3, i) represents a single bond on one side and a single or double bond on the other side, Y1 represents CR5 or CHR5a, Y2 represents N, CR4a or CHR4b, and Y3 represents NR7, CR4d or CHR4e, or ii) Y1 and Y3 may be bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a B ring, wherein the B ring represents a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and O, or an aryl ring, whereas the B ring may be substituted by one to two R4s; R2 represents xe2x80x94H, -a halogenated lower alkyl, xe2x80x94Nxe2x95x90O, -an aryl which may have one or more subsituents, or -a heteroaryl which may have one or more subsituents; R1a, R3, R4, R4a, R4b, R4d and R4e, which may be the same or different, represent a group defined by R1; and R5, R5a, R6 and R7, which may be the same or different, represent xe2x80x94H or -a lower alkyl, with proviso that when X is NR7 and R2 is an aryl having a substituent at the ortho-position, R7 may be combined with the substituent at the ortho-position to form a C2-3 lower alkylene chain, and with the aryl of R2 to form a 5- to 7-membered nitrogen-containing heterocyclic ring fused with a benzene ring(s) of the aryl group.
(2) Compounds in which n is 1 and R1 represents -a lower alkyl, -a halogen, xe2x80x94CN, xe2x80x94NO2, -a halogenated lower alkyl, xe2x80x94ORa, xe2x80x94O-a lower alkylene-an aryl, xe2x80x94CO2Ra, xe2x80x94CONRa-a lower alkylenexe2x80x94ORb, xe2x80x94CONRaRb, xe2x80x94CO-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94CONRa-a lower alkylene-NRbRc, xe2x80x94CONRa-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group) or -an aryl.
(3) Compounds in which xe2x80x9cAxe2x80x9d represents a linkage and R2 represents an aryl which may have one or more subsituents or a heteroaryl which may have one or more subsituents.
(4) Compounds in which R2 represents a phenyl which may have one or more substituents which are selected from the group consisting of -(a lower alkyl which may be substituted by xe2x80x94OH), -a lower alkenyl, -a halogen, xe2x80x94NO2, xe2x80x94CN, -a halogenated lower alkyl, xe2x80x94O-a halogenated lower alkyl, xe2x80x94OH, xe2x80x94O-a lower alkyl, xe2x80x94CO-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CONH2, xe2x80x94SO2NH2, xe2x80x94CO-an aryl, xe2x80x94SO2-an aryl, xe2x80x94NH2, xe2x80x94NH-a lower alkyl, xe2x80x94N(a lower alkyl)2, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), xe2x80x94NHCO-a lower alkyl, -an aryl which may be substituted by 1xcx9c5 substituents selected from Group E, and -a heteroaryl which may be substituted by 1xcx9c5 substituents selected from Group E.
(5) Compounds in which T represents CH and U represents CH or C-(a lower alkyl).
(6) Compounds in which X represents SO2.
(7) Compounds in which i) Y1 . . . Y2 . . . Y3 represents CR5xe2x95x90Nxe2x80x94NR6, CR5aR5bxe2x80x94NHxe2x80x94N6, CR5aR5bxe2x80x94CR4bR4cxe2x80x94N6, or ii) Y1 and Y3 of Y1 . . . Y2 . . . Y3 are bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a 5- or 6-membered monocyclic heteroaryl ring, wherein said 5- or 6-membered monocyclic heteroaryl ring may be substituted by one to two R4s.
(8) Compounds in which a chain structure or a partial structure of a monocyclic heteroaryl ring in the group, Y1 . . . Y2 . . . Y3, contains a frame which is represented by xe2x80x9cCxe2x95x90Nxe2x80x94Nxe2x80x9d, xe2x80x9cCxe2x95x90Nxe2x80x94Cxe2x80x9d or xe2x80x9cCxe2x80x94Nxe2x95x90Cxe2x80x9d, preferably xe2x80x9cCxe2x95x90Nxe2x80x94Nxe2x80x9d.
(9) Compounds in which Y1 . . . Y2 . . . Y3 represents CR5xe2x95x90Nxe2x80x94NR6, R5 represents xe2x80x94H or -a lower alkyl, and R6 represents xe2x80x94H, or a lower alkyl or alkenyl which may be substituted by one or more substituents selected from a group consisting of xe2x80x94O-a lower alkyl, xe2x80x94S-a lower alkyl, xe2x80x94SO2-a lower alkyl, xe2x80x94SO-a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl, xe2x80x94CONH2, xe2x80x94NH2, xe2x80x94NH-a lower alkyl, xe2x80x94N(a lower alkyl)2, -(a nitrogen-containing saturated heterocyclic group which may be substituted by a lower alkyl group), and -an aryl.
(10) Compounds in which Y1 and Y3 of Y1 . . . Y2 . . . Y3 are bonded with each other via 2 or 3 atoms and combined with the adjacent Y2 to form a 5-membered monocyclic heteroaryl ring which may be substituted by one to two R4s selected from the group consisting of -a lower alkyl, xe2x80x94COOH, xe2x80x94COO-a lower alkyl, xe2x80x94CO-a lower alkyl and xe2x80x94SO3H.
(11) Compound having an inhibition activity (IC50) of 5 xcexcM or less as determined by the method of the Melanoma cell growth inhibition test (Test example 3).
Among the compounds of the present invention, preferred ones are listed below: 3-(6-Bromo-2-methylimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-1-yl 2-methyl-5-nitrophenyl sulfone; 3-(6-bromoimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-1-yl 2-methyl-5-nitrophenyl sulfone; 2xe2x80x2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2,2-dimethyl-5-nitrobenzenesulfonohydrazide; 2xe2x80x2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-2-ethyl-1xe2x80x2-methyl-5-nitrobenzenesulfonohydrazide; 3-({2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-1-methylhydrazino}sulfonyl)4-methylbenzonitrile; 2xe2x80x2-[(6-fluoroimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2,2-dimethyl-5-nitrobenzenesulfonohydrazide; 2-amino-2xe2x80x2-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2-methyl-5-nitrobenzenesulfonohydrazide; 2xe2x80x2-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2-methyl-5-nitro-2-(2,2,2-trifluoroethoxy)benzenesulfonohydrazide; 6-chloro-3-[2-(2-methyl-5-nitrobenzenesulfonyl)thiazol-4-yl]imidazo[1,2-a]pyridine; 6-bromo-3-{[(2-methyl-5-nitrobenzenesulfonyl)(2-morpholinoethyl)hydrazono]methyl}imidazo[1,2-a]pyridine; 6-chloro-3-{[(methyl)(2-methyl-5-nitrobenzenesulfonyl)hydrazono]methyl}imidazo[1,2-a]pyridine; 3-{[(methyl)(2-methyl-5-nitrobenzenesulfonyl)hydrazono]methyl}imidazo[1,2-a]pyridine-6-carbonitrile; 5-cyano-2xe2x80x2-[(6-fluoroimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2,2-dimethylbenzenesulfonohydrazide; 5-cyano-2xe2x80x2-[(6-cyanoimidazo[1,2-a]pyridin-3-yl)methylidene]-1xe2x80x2,2-dimethylbenzenesulfonohydrazide; 1xe2x80x22-dimethyl-2xe2x80x2-[(6-methylimidazo[1,2-a]pyridin-3-yl)methylidene]-5-nitrobenzenesulfonohydrazide; 2xe2x80x2-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methylidene]-2-(1H-imidazol-1-yl)-1xe2x80x2-methyl-5-nitrobenzenesulfonohydrazide; 2xe2x80x2-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methylidene]-2- dimethylamino-1xe2x80x2-methyl-5-nitrobenzenesulfonohydrazide; and salts thereof.
The compounds of the present invention may be geometric isomers or tautomers depending upon the kind of substituents. The present invention also covers these isomers in separated forms and the mixtures thereof. Furthermore, some of the compounds may contain an asymmetric carbon in the molecule; in such a case isomers could be present. The present invention also embraces the mixtures of these optical isomers and the isolated forms of the isomers.
Some of the compounds of the invention may form salts. There is no particular limitation so long as the formed salts are pharmacologically acceptable. Specific examples of acid addition salts are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, etc. Specific examples of basic salts include salts with inorganic bases containing metals such as sodium, potassium, magnesium, calcium, aluminum, etc., or salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, etc. The present invention further embraces various hydrates and solvates to the compounds (I) or salts thereof of the invention as well as polymorphism thereof
(Processes for producing compounds)
Hereinafter representative processes for producing the compounds of the present invention are described below. In these processes, functional groups present in the starting materials or intermediates may be suitably protected with protective groups, depending upon the kind of functional groups. In view of the preparation technique, it may be advantageous to protect the functional groups with groups that can readily be reverted to the original functional groups. When required, the protective groups are removed to give the desired products. Examples of such functional groups are amino, hydroxy, carboxy, etc. Examples of the protective groups which may be used to protect these functional groups are shown in, e.g., Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, second edition. These protective groups may be appropriately employed depending upon reaction conditions. 
(Here and hereinafter, the B 1 ring represents a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and O, or a nitrogen-containing saturated heterocyclic ring, said B ring may be substituted by one to two R4s and Y3 is an N atom; and L represents a leaving group.)
The compounds (Ia), (Ib), and (Ic) of the present invention may be prepared by subjecting heterocycle derivatives shown by general formula (II) to various modification reactions such as sulfonylation, amidation, and alkylation according to a conventional manner.
In the above formula, a leaving group shown by L is a halogen (fluorine, chlorine, bromine, iodine, etc.) or a sulfonyloxy group (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy, toluenesulfonyloxy, benzenesulfonyloxy, etc.), and preferably chlorine, bromine, iodine, and trifluoromethanesulfonyloxy. These leaving groups are appropriately selected depending on the kind of starting material or reaction.
Sulfonylation reaction may be performed by reacting heterocycle derivatives (II) with reactive derivatives of sulfonic acid according to a conventional manner. The reactive derivatives of sulfonic acid include sulfonyl chloride as a most ordinary example, as well as sulfonyl bromides, acid anhydrides (sulfonic anhydride prepared from two molecules of sulfonic acid), acid azides, and the like. Such reactive derivatives of sulfonic acid may be readily obtained from the corresponding sulfonic acid in a conventional manner. An example in which sulfonyl chloride is prepared includes a method described in J. Chem. Soc. Pak., 8(1), 11-17(1986), and Bull. Chem. Soc. Jpn., 59(2), 465-70 (1986). Alternative prepare sulfonyl chloride include a method in which chlorosulfonic acid is employed as a reaction agent, such as those described in Org. Synth., 1941, I, 85 or J. Med. Chem., 33(9), 2569-78(1990), and the Sandmeyer reaction via a diazonium salt as described in Tetrahedron Lett., 31(26), 3714-18(1990) or J. Am. Chem. Soc., 112(12), 4976-7(1990).
In the case of using acid halides as the reactive derivatives for sulfonylation, the sulfonylation is performed preferably in the presence of a base (an inorganic base such as sodium hydroxide, sodium hydride, etc., or an organic base such as pyridine, triethylamine (TEA), diisopropylethylarmine, etc.). When the pyrazole derivatives (II) are reacted with reactive derivatives such as acid anhydrides or acid azides, the sulfonylation may be carried out in the absence of a base. Alternatively, the reaction may be performed in the presence of a base such as sodium hydride, TEA, pyridine or 2,6-lutidine. The reaction temperature may be appropriately chosen depending on the kind of reactive derivatives used. As a solvent that may be used, there are basic solvents such as pyridine; an aromatic hydrocarbon solvent such as benzene or toluene; an ether solvent such as tetrahydrofuran (TEF), 1,4-dioxane, etc.; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, etc.; an amide solvent such as N, N-dimethylformamide (DMF), N,N-dimethylacetamide, etc.; a carbonyl-based solvent such as acetone, methyl ethyl ketone, etc. These solvents may be used alone or as an admixture of two or more. The solvent should be appropriately chosen depending on the kind of starting compounds.
The amidation reaction may be performed in a conventional manner, preferably by converting carboxylic acid into reactive derivatives such as acid halides (acid chlorides, etc.) or acid anhydrides, and then reacting the reactive derivatives with the heterocycle derivatives (II). In the case of using reactive derivatives of carboxylic acid, the aforementioned base is preferably added. Further, amidation of the heterocycle derivatives (II) with carboxylic acids may be carried out in the presence of condensation agent (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), 1,1xe2x80x2-carbonylbis-1H-imidazole (CDI), etc.). At this time, an additive such as 1-hydroxybenzotriazole (HOBt) or the like may be added. The reaction temperature may be appropriately chosen depending on the kind of starting compounds. As a solvent, an inert solvent to the reaction may be used, e.g. the solvent used in the above sulfonylation. These solvents may be used alone or as an admixture of two or more. The solvent should be chosen depending on the kind of starting compounds.
Alkylation may be performed in a conventional method, and preferably in the presence of the aforementioned base such as potassium carbonate, sodium hydroxide, sodium hydride, or the like. An alkylating agent such as alkyl halide or sulfonate (an ester of p-toluenesulfonic acid, an ester of trifluoromethanesulfonic acid, etc.) may be employed. The reaction may be conducted under cooling or heating or at room temperature. As a solvent, an inert solvent to the reaction may be used, e.g. the solvent used in the above sulfonylation. These solvents may be used alone or as an admixture of two or more. The solvent should be chosen depending on the kind of starting compounds. Further, when alkylation gives a monoalkylated compound, the compound can be converted to a dialkyl compound using a conventional alkylation reaction again. Moreover, when aldehydes or ketones are used as a reaction agent, reductive alkylation can be performed by using reducing agents such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, dehydrator to give the corresponding imine and then reducing the imine by sodium borohydride. The reductive alkylation also can be performed by using a Deanxe2x80x94Stark.
The starting compounds (II), which are heterocycle derivatives, may be prepared in a conventional manner in accordance with the type of each heterocycle. Representative production methods are illustrated below: 
(Alk represents an alkyl group, and Rxe2x80x2 represents an alkyl or aryl group.)
The pyrazole derivatives (IIa) are synthesized by reacting acyl compounds (3) with N,N-dimethylformamide dimethylacetal, etc., to give dimethylamino-enone compounds and further adding hydrazine to the enone compounds for cyclization. The reaction may be conducted either in the absence of any solvent or in the presence of an organic solvent inert to the reaction. The reaction may be performed under cooling or heating or at room temperature. Acyl compounds (3) in which U represents CR3 can be obtained by a reaction of amino compounds (1) with diketone compounds (2). It can be also obtained by a method in which a halogenated ketone alkylates N-pyridylamidine as described in Synthesis, 263-265 (1984). Alternatively, acyl compounds (3) can be obtained by an acylation reaction of Friedel-Crafts types to imidazopyridine derivatives (5). The acylation reaction may be performed in a conventional manner. For example, a method according to J. Med. Chem., 13, 1048 (1970) may be employed. The compound (5) may be easily prepared using aminopyridine derivatives (1) and xcex1-halogenated carbonyl compounds (4) in a conventional manner.
Acyl compounds (3) in which U represents N can be obtained by oxidative cleavage of a double bond of olefin compounds (8), e.g., via ozonolysis. At the time, depending upon starting compounds and reaction conditions, ketone equivalents such as hemiketals may be separated. In these cases, such compounds can be changed to desired acyl compounds using appropriate reaction conditions. Olefin compounds (8) can be synthesized by heating hydrazides (7) in acetic acid as an example. Hydrazides (7) can be synthesized by acylation of hydrazines (6) in a conventional method. 
The starting compounds (IIb) can be synthesized by heating hydrazide compounds (9) in acetic acid as an example to cyclize them. Hydrazide compounds (9) can be synthesized by acylation of hydrazines (6) in a conventional method. 
The starting compounds (IIc-1) can be synthesized by reacting enone compounds (11) with tosylmethylisocyanide (TosMIC) in a conventional method and compounds (11) can be synthesized by subjecting compounds (10) to the Homer-Emmons-Wadsworth reaction in a conventional method. As for compounds (10), the synthesis method of said compounds (3) can serve basically as a reference. Differences lie in that when U represents C-R3, hormylation by the Vilsmeier reaction is employed instead of the acylation of compounds (5) and in that when diketone reacts with compounds (1) to create an imidazopyridine ring, halogenated malonoaldehyde is employed as a reaction agent. Examples of the Vilsmeier reaction includes a method described in the aforementioned J. Med. Chem., 13, 1048(1970). When U represents N, compounds with R5representing H can be utilized in the synthesis of compounds (3) as the starting compounds to give compounds (10). The starting compounds (IIc-2) can be synthesized by subjecting ester compounds (IIc-1) to hydrolysis and decarboxylation with heating. 
(Here and hereinafter, R61 represents a group as defined for R6, other than H.)
In this process, hydrazone derivatives shown by the formula (III) is subjected to various modification reactions such as sulfonylation or amidation according to a conventional manner to obtain compounds (Id) and (If) of the present invention. When R6 represents H, the compounds (Id) and (If) of the present invention can be led to invented compounds (Ie) and (Ig) by known methods of a functional group transformation, such as alkylation, etc., as desired.
These sulfonylation, amidation, and alkylation may be conducted in the same manner as in the Production Method I. 
The starting compounds (III), which are hydrazone derivatives, may be synthesized in a conventional manner by reacting acyl compounds (3) or (10) with hydrazine compounds shown by NH2NHR6 or its hydrate, preferably in an alcohol solvent such as methanol or ethanol under cooling or heating or at room temperature. 
This is a process for obtaining aminothiazole derivatives (Ih) by subjecting xcex1-halogenated ketone, etc., shown by a formula (IV) to a cyclization reaction with thiourea.
The cyclization reaction may be conducted in a conventional manner. For example, thiourea compounds or the like are reacted with xcex1-halogenated ketone (IV) or the like in solvents or without any solvent under cooling or heating or at room temperature. Preferable solvents are alcohol solvents such as methanol, ethanol and isopropanol, the above carbonyl-based solvents, ether solvents, halogenated hydrocarbon solvents, amide solvents, etc. The solvent should be appropriately chosen depending on the kind of starting compounds, and these solvents may be used alone or as an admixture of two or more. The reaction sometimes proceeds smoothly by adding a base (potassium carbonate, sodium carbonate, TEA, etc.). 
The starting compounds (IV), which are xcex1-halogenated ketone derivatives, may be synthesized by halogenation of acyl compounds (3a) in a conventional manner. Halogenation reagents are, for example, chlorine, bromine, iodine, copper bromide (II), potassium iodate, benzyltrimethylammonium tribromide, phenyltrimethylammonium tribromide, tetrabutylamnmonium tribromide, sulfuryl chloride, trimethylsilyl chloride, trimethylsilyl bromide, and 5,5-dibromobarbituric acid. As a solvent, a solvent inert to the reaction may be used, for example, acidic solvents such as acetic acid and hydrobromic acid/acetic acid, the aforementioned alcohol solvents and ether solvents. The reaction temperature may be under cooling or heating or at room temperature.
The desired starting compound may also be prepared by appropriately known methods to convert substituents, wherein proper methods may depend on the kind of substituents. 
This is a process for obtaining a compound (Ii) of the present invention by subjecting xcex1-halogenated ketone, etc., shown by a formula (V) to a cyclization reaction with thiourea. The cyclization reaction may be performed in the same manner as in Production Method III. The starting compound (V) may be synthesized in the same manner as the starting compound (IV). 
(Here and hereinafter, the B2 ring represents a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and O, a nitrogen-containing saturated heterocyclic ring, a nitrogen-containing saturated heterocyclic group or an aryl ring, whereas said B2-ring may be substituted by one to two R4s and Y3 is a C atom.)
This process is for obtaining a compound (Ij) of the present invention by subjecting amino compounds shown by the formula (V) to an alkylation or arylation reaction. The alkylation reaction may be performed in a conventional manner, for example, the same manner as that in Production Method I. Further, known converting methods such as N-alkylation or the like may be appropriately performed. Examples of the arylation reaction include coupling reactions described in Acc. Chem. Res., 31, 805, (1998) and ibid. 31, 852 (1998) and ipso-substitution described in J. Org. Chem., 63(18), 6338(1998). The starting amino compounds (VI) can be synthesized according to a conventional method. For example, when the B2-ring is an imidazole, they can be synthesized using the aforementioned xcex1-halogenated ketone (IV) as a starting material in a conventional method, for example, a method described in J. Org. Chem. 59(24) 7299-7305 (1994). When the B2-ring is a thiazole ring, they can be produced by reacting unsubstituted thiourea as a reaction agent according to the method described in the aforementioned Production Method IV. 
(Here and hereinafter, Y21 represents NH or CR4aR4b.)
This process is for synthesizing compounds (Ik) and (Im) of the present invention by subjecting amine derivatives shown by the formula (VII) to various modification reactions of sulfonylation and amidation according to conventional methods. Further, the compounds (Ik) and (Im) of the present invention can be led to compounds (In) and (Ip) of the present invention, respectively, by known methods of a substituent conversion, such as alkylation or the like. Sulfonylation, amidation, and alkylation can be conducted, for example, in the same manner as in Production Method I. The starting compounds (VI) can be readily sythensized using the methods shown by the synthetic routes below as an example. 
The starting material (VIIa) can be readily synthesized, as an example, by subjecting the nitrile compounds (15) to reducing reactions described in Jikken Kagaku Kouza (Encyclopedia for Experimental Chemistry) edited by Nihon Kagaku Kai (Japanese Association of Chemistry) and published by Maruzen Co., Ltd. The nitrile compounds (15) can be produced by subjecting the aforementioned acyl compounds (3) to a conventional method such as one described in J. Med. Chem. 12, 122 (1969). The compounds (VIIb) can be synthesized by reacting the ester compounds (16) with hydrazines at room temperature or under heating. The compounds (VIIc) can be synthesized by reducing xcex1-halogenated ketone derivatives (IV) with an agent such as sodium borohydride to give epoxide or halohydrin compounds, followed by the treatment with amino compounds. 
(Here and hereinafter, the B ring represents a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 hetero atoms selected from the group consisting of N, S, and O, a nitrogen-containing saturated heterocyclic ring, an aryl ring, whereas the B ring may be substituted by one to two R4s.)
This process is for converting thiol compounds (VIII) to the compounds of the present invention (Iq) and conducting an oxidation reaction as necessary to synthesize sulfoxide derivatives and sulfone derivatives shown by the formula (Ir) and (Is). Examples of methods to synthesize sulfide compounds (Iq) from the starting materials, thiol compounds (VIII), include a method in which reacting them with halogenated alkyl or halogenated aralkyl in the presence of a base according to a conventional method when the group, xe2x80x94Axe2x80x94R2, is an alkyl or aralkyl. When the group, xe2x80x94Axe2x80x94R2, is an aryl or heteroaryl, sulfide compounds (Iq) can be obtained by a coupling reaction with an halogenated aryl. For the coupling reaction, for example, a method according to J. Org. Chem. 1993, 58(12), 3229-3230, and Synth Commun. 1982, 12(13), 1071 may be used when the halogen is fluorine, a method according to Synthesis 11, 892 (1981) may be used when the halogen is bromine, and a method according to Chem. Lett. 11, 1363 (1980) may be used when the halogen is iodine. Moreover, a method can be employed in which the thiolate salts (VIII) are reacted with diazonium salts, and an ipso-substitution reaction can be so employed in which an aryl group having appropriate leaving groups is subjected to thiolate salts at room temperature or under heating. As for the reaction conditions, methods can be referenced which are described, for example, in Japanese patent KOKAI (Laidxe2x80x94Open) No. 2000-53635 and Tetrahedron Lett., 26, 6365 (1985).
The oxidation reaction to convert (Iq) to (Ir) and (Is) may be performed according to a conventional method, and an oxidizing agent such as m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, potassium permanganate, oxone and sodium periodate may be used. In case with compounds which are not easily oxidized, the reaction conditions, for example, described in J. Heterocyclic Chem., 28, 577 (1991) and Tetrahedron Lett., 35, 4955 (1994) may be referenced. In the case that a functional group other than the aimed sulfide is oxidized and, for example, converted to an oxidant such as N-oxide upon the oxidation reaction, it can be deoxidized with an appropriate reducing agent according to a conventional manner.
The starting compounds (VIII) may be synthesized according to conventional methods. For example, when the B ring is a heteroaryl, the methods for thiazol described in Bioorganic and Medicinal Chemistry, 5, 601 (1997) and J. Org. Chem., 13, 722 (1948), those for imidazole described in J. Am. Chem. Soc., 71, 4000 (1949), J. Indian Chem. Soc., 52(12), 1117 (1981) and Chem. Pharm. Bull., 32(7), 2536 (1984), those for oxazole described in Fr1450443 (1965), JCS Perkin Trans. 1,3, 435 (1984), Chem. Pharm. Bull., 40, 245 (1992) and Bull. Soc. Chim. Belges., 70, 745 (1961); and those for thiadiazole described in Chem. Ber., 94, 2043 (1961) may be referenced for their synthesis. Compounds with other rings can be synthesized by constructing a B ring by methods described in, for example, xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d edited by Katritzky, Rees, xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9d edited by A. Weissberger, and E. C. Taylor, or xe2x80x9cAdvanced in Heterocyclic Chemistryxe2x80x9d edited by A. R. Katritzky. 
(Here, Hal represents a halogen.)
This process is for converting halogenated aryl compounds shown by the formula (IX) and (X) by a coupling reaction according to a conventional manner to the compounds (It) of the present invention. The coupling reaction can be conducted according to a conventional method. The coupling reaction is preferably performed in the presence of a catalyst such as palladium, nickel or copper after (IX) or (X) is converted to a reactive derivative such as an aryl metal reagent, an arylboronic acid derivative or an aryl tin compound in a conventional manner. An example of these coupling reactions is a method described in Jikken Kagaku Kouza as described hereinbefore. The starting compounds (IX) may be synthesized by constructing a B ring by methods described in, for example, xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9d or xe2x80x9cAdvanced in Heterocyclic Chemistryxe2x80x9d as described hereinbefore, and then by employing, as necessary, the alkylation reaction, coupling reaction, oxidizing reaction, deoxygenation reaction which are described in Production Method VII.
The desired compound of the present invention may also be prepared by functional group transformation methods well known to those skilled in the art, which may depend on the kind of the substituent. The order of the reactions, or the like, may be appropriately changed in accordance with the aimed compound and the kind of reaction to be employed.
The other compounds of the present invention and starting compounds can be easily produced from suitable materials in the same manner as in the above processes or by methods well known to those skilled in the art.
Each of the reaction products obtained by the aforementioned production methods is isolated and purified as a free base or a salt thereof. The salt can be produced by a usual salt forming method. The isolation and purification are carried out by employing usually used chemical techniques such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like.
Various forms of isomers can be isolated by the usual procedures making use of physicochemical differences among isomers. For instance, racemic compounds can be separated by means of a conventional optical resolution method (e.g., by forming diastereomer salts with a conventional optically active acid such as tartaric acid, etc. and then optically resolving the salts) to give optically pure isomers. A mixture of diastereomers can be separated by conventional means, e.g., fractional crystallization or chromatography. In addition, an optical isomer can also be synthesized from an appropriate optically active starting compound.
The compounds of the present invention exhibit a kinase inhibitory activity, especially PI3K inhibitory activity and therefore, can be utilized in order to inhibit abnormal cell growths in which PI3K plays a role. Thus, the compounds are effective in the treatment of disorders with which abnormal cell growth actions of PI3K are associated, such as restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the compounds of the present invention possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.
The pharmacological effects of the compounds accordingto the invention have been verified by the following pharmacological tests.
Test Example 1 Inhibition of PI3K (p110xcex1 Subtype)
Inhibition was determined using enzyme (bovine p110xcex1) prepared in the baculovirus expression system. Bovine p110xcex1 was prepared according to a modification from the method by I. Hiles et al., Cell, 70, 419 (1992). Each compound to be assayed was dissolved in dimethylsulfoxide (DMSO) and the obtained 10 mM DMSO solution was serially diluted with DMSO. The compound (0.5 xcexcl) to be assayed and enzyme were mixed in 25 xcexcl of buffer solution (40 mM Tris-HCl (pH 7.4), 200 mM NaCl, 2 mM dithiothreitol, 5 mM MgCl2). Then, 25 xcexcl of 5 mM Tris-HCl (pH 7.4) buffered solution supplemented with 10 xcexcg PI (Sigma), 2 xcexcCi[xcex3-32P] ATP (Amersham Pharmacia) and 80 xcexcM non-radiolabeled ATP (Sigma) was added to the mixture to initiate the reaction. After reacting at 37xc2x0 C. for 15 minutes, 200 xcexcl of 1M HCl and 400 xcexcl of CHCl3/MeOH (1:1) were added to the reaction mixture. The resulting mixture was stirred and then centrifuged. After the organic layer was extracted twice with 150 xcexcl of MeOH/1M HCl (1:1). The radioactivity was measured using Cerenkov light.
The IC50 inhibition activity was defined by a 50% inhibition concentration of each compound assayed, which was converted from the radioactivity determined as 100% when DMSO alone was added and as 0% when no enzyme was added.
The compounds of the present invention showed excellent inhibitory activities. For example, Compound 6 of the present invention inhibits PI3K more than 10 times as strong as known PI3K inhibitor LY294002.
Test Example 2 Colon Cancer Cell Growth Inhibition
HCT116 cells from a colon cancer cell line were cultured in McCoy""s 5A medium (GIBCO) supplemented with 10% fetal bovine serum. HCT116 cells were inoculated on a 96 well plate (5000 cells/well) followed by overnight incubation. The test compound diluted with the medium was added to the medium in a final concentration of 0.1 to 30 xcexcM (final DMSO concentration, 1%). After incubation for over 72 hours, Alamar Blue reagent was added to the medium. Two hours after the addition, a ratio of fluorescent intensity at an excitation wavelength of 530 nm to that at an emission wavelength of 590 nm was measured to determine the IC50.
Compounds 5, 6, 8, and 9 of the present invention exerted a good cancer cell growth inhibition activity.
Test Example 3 Melanoma Cell Growth Inhibition
A375 cells from a melanoma cell line were cultured in DMEM medium (GIBCO) supplemented with 10% fetal bovine serum. A375 cells at 10,000 cells/100 xcexcl were added to a 96 well plate which contained 1 xcexcl/well of the test compounds (final concentration of 0.001xcx9c30 xcexcM). After incubation for over 46 hours, Alamar Blue reagent was added to the medium (10 xcexcl/well). Two hours after the addition, a ratio of fluorescent intensity at an excitation wavelength of 530 nm to that at an emission wavelength of 590 nm was measured to determine the IC50 of the test compounds in the same manner as in the above examples.
Compounds 6, 30, 43, 53, 54, 57, 59, 60, 65, 77, 88, 93, 95, 96, 99, 112 and 113 of the present invention exerted a good melanoma cell growth inhibition activity. Their IC50 values were less than 1 xcexcM. Contrarily, the known PI3K inhibitor LY294002 showed a value of 8.39 xcexcM.
In addition to the above cancer cell lines, the compounds of the present invention exhibited excellent cancer cell growth inhibiting activities against Hela cells from a cervix cancer cell line, A549, H460 cells from a lung cancer cell line, COLO205, WiDr, Lovo cells from a colon cancer cell line, PC3, LNCap cells from a prostate cancer cell line, SKOV-3, OVCAR-3, CH1 cells from an ovary cancer cell line, U87 MG cells from a glioma cell line and BxPC-3 cells from a pancreas cancer cell line.
Test Example 4 In Vivo Anti-tumor Activities
A single-cell suspension of HelaS3 (5xc3x97106 cells), a human cervix cancer cell line, was inoculated into the flank of female Balb/c nude mice by subcutaneously injection. When the tumor reached 100xcx9c200 mm3 in volume, test compounds were intraperitoneally administered once a day for two weeks. 20% Hydroxypropyl-xcex2-cyclodextrin/saline was intraperitoneally administered with the same schedule as a control group. The diameter of the tumors was measured with a vernier caliper at certain time intervals until one day after the final doze administration. The tumor volume was calculated by the following formula: 1/2xc3x97(a shorter diameter)2xc3x97(a longer diameter).
In the present test, test compounds exhibited superior anti-tumor activities as compared with the control group.
The pharmaceutical composition of the present invention can be prepared in a conventional manner by mixing one or more compounds of the invention shown by general formula (I) with a carrier for medical use, a filler and other additives usually used in pharmaceutical preparations. The pharmaceutical composition of the invention may be administered either orally in the form of tablets, pills, capsules, granules, powders, liquid, etc., or parenterally such as by intravenous or intramuscular injection, in the form of suppositories, or through pemasal, permucosal or subcutaneous route.
For oral administration of the composition in the present invention, a solid composition in the form of, e.g., tablets, powders or granules is available. In such a solid composition, one or more active or effective ingredients are blended with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or magnesium aluminate metasilicate. The composition may further contain additives other than the inert diluent by the usual procedures. Examples of such additives include a lubricant such as magnesium stearate, a disintegrating agent such as calcium cellulose glycolate, a solubilization assisting agent such as glutaric acid or aspartic acid. Tablets or pills may be coated, if necessary, with films of sugar or a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, etc.
A liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and contains an inert diluent conventionally employed, e.g., purified water or ethanol. In addition to the inert diluent above, the liquid composition may further contain an auxiliary agent such as a moistening agent or a suspending agent, a sweetener, a flavor and/or a preservative.
A composition for parenteral administration contains a sterile aqueous or non-aqueous solution, a suspension and an emulsion. Examples of the aqueous solution and suspension include distilled water for injection use and physiological saline. Typical examples of the non-aqueous solution and suspension are propylene glycol, polyethylene glycol, vegetable oil such as olive oil, an alcohol such as ethanol, polysorbate 80, and the like. These compositions may further contain a preservative, a moistening agent, an emulsifier, a dispersing agent, a stabilizer and a solubilization assisting agent. These compositions are sterilized, e.g., by filtering them through a bacteria retention filter, incorporating a bactericide or through irradiation. Alternatively, they may be prepared into a sterile solid composition, which is dissolved in sterile water or a sterile solvent for injection prior to use.
In the case of oral administration, suitable daily does is usually about 0.0001 to 50 mg/kg body weight, preferably about 0.001 to 10 mg/kg, more preferably about 0.01 to 1 mg/kg, and the daily does is administered once a day or divided into 2 to 4 doses per day. In the case of intravenous injection, suitable daily dose is usually about 0.0001 to 1 mg/kg body weight, preferably about 0.0001 to 0.1 mg/kg. And the daily dose is administered once a day or divided into a plurality of doses per day. The dose may be appropriately determined for each case, depending on conditions, age, sex, etc.
The compounds of the present invention can be utilized alone, or in conjunction with other treatments (e.g., radiotherapy and surgery). Moreover, they can be utilized in conjunction with other antitumor agents, such as alkylation agents (cisplatin, carboplatin, etc.), antimetabohites (methotrexate, 5-FU, etc.), antitumor antibiotics (adriamymycin, bleomycin, etc.), antitumor vegetable alkaloids (taxol, etoposide, etc.), antitumor hormones (dexamethasone, tamoxifen, etc.), antitumor immunological agents (interferon xcex1, xcex2, xcex3, etc.), and so forth.